The present invention relates to novel pharmaceutical compositions of macrolide immunosuppressants such as tacrolimus. It further relates to pharmaceutical compositions which are capable of solubilising poorly soluble macrolide immunosuppressants, and which are suitable for topical administration. In further aspects, the invention relates to the therapeutic uses of such compositions.
Immunosuppressants are pharmaceutical compounds that reduce the activity of the immune system. They are commonly used in the therapy of autoimmune diseases and in the prophylaxis and treatment of organ transplants. Autoimmune diseases are conditions which are believed to involve some type of hypersensitivity of the immune system, which is today, for example, known for Crohn's disease, multiple sclerosis, rheumatoid arthritis, ulcerative colitis, Addison's disease and numerous other conditions. After an organ transplantation, the immune system of the recipient nearly always identifies the new organ as foreign and potentially hostile material due to differences in human leukocyte antigen haplotypes between the donor and recipient, and attempts to remove it by attacking and destroying its cellular components.
The immunosuppressants that have been developed for therapeutic use may be classified according to their chemical structure and/or their mechanism of action. Among the early immunosuppressants were in particular antimetabolites, such as azathioprine (a purine synthesis inhibitor) and methotrexate (an antifolate). Substantial therapeutic benefit for transplant recipients was brought about by the advent of the first macrolides, in particular ciclosporin, and later tacrolimus. Further immunosuppressive compounds with related structure and activity include pimecrolimus, everolimus, sirolimus, deforolimus, everolimus, temsirolimus, and zotarolimus. More recently, antibodies and fusion proteins against various cellular and non-cellular targets that are involved in immune responses, such as infliximab, etanercept, rituximab, tocilizumab, and abatacept, have been developed and introduced to the drug market.
Macrolide immunosuppressants such as tacrolimus, sirolimus, everolimus and the like, while being highly active once they are absorbed into the organism or target tissue, are challenging compounds to formulate and deliver to the site of action, in particular due to their poor solubility and relatively large molecular size. For systemic therapy via the oral or intravenous routes of administration, they are typically presented as solubilised formulations comprising substantial amounts of solubilising excipients, such as surfactants and organic solvents.
Tacrolimus, a compound of particular interest in the context of the present invention, was first developed as a concentrate for intravenous infusion after dilution, and as an oral hard capsule formulation. In the concentrate for infusion (currently marketed by Astellas as e.g. Prograf®), tacrolimus (5 mg) is solubilised in a mixture of ethanol (638 mg) and macrogolglycerolricinoleate (200 mg), which excipients are not well tolerated by many patients, but are still considered necessary in view of the very poor solubility of the drug substance. These systemic formulations are used for the prophylaxis and treatment of organ transplant rejection, most frequently with patients that have received a kidney, liver or heart transplant.
More recently, tacrolimus has been developed as an ointment for the treatment of atopic dermatitis. The formulation that is currently marketed (e.g. in Germany since 2002 by Astellas as Protopic®) is available in two strengths (0.3 mg/g and 1 mg/g, respectively), and contains the excipients vaseline, liquid paraffin, solid paraffin, wax, and propylene carbonate.
The therapeutic effectiveness of tacrolimus in the treatment of atopic dermatitis was demonstrated in various placebo-controlled multicentric clinical studies with adult patients in the USA and Europe (1, 4), as well as with children of 3 to 6 years (23, 25). Topical tacrolimus also appears to be effective in the treatment of contact dermatitis (15, 16). In contrast, the experimental use of topical tacrolimus for psoriasis treatment has generally not been successful, even though psoriasis has been clearly identified as an autoimmune disease, possibly due to the thickness and structure of the psoriasis plaques which may represent considerable diffusion barriers for the penetration and uptake of the active ingredient (11, 30). Only in some special cases, relatively positive results were obtained, e.g. by applying occlusive conditions (22), using a liposomal formulation (8), or by treating the relatively thin facial skin or administering the medicine into wrinkles (10, 14, 17, 18, 26, 28, 29).
It is noted, however, that such special cases are associated with a number of drawbacks. For example, skin occlusion is not only considered as unpleasant by the patients, but also poorly feasible for certain areas of the skin (e.g. the face, in folds, near joints etc.), and generally unacceptable in the case of large or multiple affected sites. Liposomal formulations are disadvantageous in that they are not easily manufactured in a reproducible manner at an industrial scale. Moreover, they are difficult to sterilise or produce under aseptic conditions, which could be desirable as the product is not used on intact skin but on adversely affected skin. Treating only certain sites of the affected skin is obviously associated with the disadvantage that other affected sites remain untreated or poorly treated.
The limited effectiveness of conventional ointment formulations of tacrolimus is also indicated by the fact that the currently available topical tacrolimus product (Protopic®) is only approved for the treatment of atopic dermatitis, not of psoriasis.
Other macrolide immunosuppressants are, like tacrolimus, poorly soluble and relatively large molecules which are also difficult to formulate and which are likely to possess the same limitations with respect to penetrating psoriasis plaques. None of these compounds have been successfully developed as topical formulations for psoriasis treatment.
Consequently, there is a need for improved topical formulations of macrolide immunosuppressive compounds such as tacrolimus which are suitable for, and effective in, the treatment of other conditions than atopic dermatitis. In particular, there is a need for topical medicines for treating psoriasis, using formulations which do not require occlusion, incorporate liposomes, which are easily manufactured at large scale, and/or which do not possess one or more of the disadvantages of the compositions that are known today.
It is an object of the present invention to provide such compositions. Further objects are to provide beneficial uses of compositions of macrolide immunosuppressive compounds and methods for preparing such compositions. Still further objects will be understood in the light of the description and the patent claims.
It is noted that WO 03/053405 A1 discloses emulsions for ophthalmic use and proposed for the treatment of dry eye syndrome. The emulsions have a droplet size of 150 nm to 250 nm (p. 7, line 13) and are therefore conventional emulsions which, in contrast to microemulsions, do not form spontaneously, and are thermodynamically unstable and optically anisotropic. Moreover, the emulsions comprise more than 90% water and a cationic surfactant. There is no hint that these compositions could be useful for administration to the skin.
EP 1 929 996 A2 also describes o/w-type emulsions for ophthalmic use. The emulsions have a preferred particle size of 100 nm to 250 nm (p. 4, paragraph [0038]) and are prepared by conventional emulsification techniques requiring the input of energy (p. 5, paragraph [0043]), which lead to convention emulsions which are, in contrast to microemulsions, thermodynamically unstable and optically anisotropic. The document does not disclose the use of the emulsions for treating the skin.
WO 2006/062334 A1 discloses so-called microemulsion pre-concentrates (also known as self-microemulsifying drug delivery systems or SMEDDS) which, upon the addition of an aqueous phase, spontaneously form microemulsions. The pre-concentrates are filled e.g. into capsules and are for oral administration. The inventors of the pre-concentrates had found that the compositions lead to higher systemic bioavailability of tacrolimus after oral ingestions.
US 2003/0143250 A1 describes microemulsion pre-concentrates comprising the active ingredient, ciclosporin, which achieve a high systemic bioavailability and low inter-subject variability of the incorporated drug after oral administration (p. 18, paragraphs [0257] to [0259]. The document does not disclose other drugs that ciclosporin.
GB 2 315 216 A relates to self-microemulsifying and microemulsion composition of tacrolimus for oral administration. Again, the compositions achieve improved pleasma levels of the incorporated drug substance. The document does not teach other uses than oral administration.
US 2003/0059470 A1 teaches o/w-emulsions that are prepared by conventional processes and have droplet sizes in a range of 100 nm up to 10 μm, preferably of 200 nm to 500 nm, and are thus thermodynamically unstable and optically anisotropic (p. 5, paragraph [0075]).
WO 2006/123354 A2 provides water-free self-microemulsifying compositions (or microemulsion pre-concentrates, or SMEDDS) of hydrophobic drugs for oral use which may form microemulsions upon addition of an aqueous phase. The document does not teach other uses than oral administration.